PROJECT SUMMARY Alzheimer?s disease (AD) is a major cause of death and a significant source of financial and health burden among the elderly. There is no cure for AD. With the number of US adults ?65 doubling in the coming years, the need for better prevention and treatment strategies is paramount. Epidemiologic and genetic studies have identified several modifiable (e.g., vascular health, education, physical activity, mental activity, to name a few) and non- modifiable risk factors associated with AD risk. The strongest genetic risk factor identified to date for late-onset AD is the APOE e4 allele. APOE regulates cholesterol in the brain, and it binds to the amyloid-? peptide, a known major component of amyloid plaques found in AD patients. Major drug discovery efforts have focused on the amyloid-? and neuroinflammation pathways based on, in part, these basic AD discovery efforts, but no therapies have emerged that prevent or substantially change the trajectory of disease development among early AD patients. New basic discovery studies are needed to better understand the etiology and pathophysiology of AD to create new avenues of drug targets. Variability in the immune system?s response is an emerging factor in the development of AD. AD genome-wide studies reflect an enrichment of genes related to the innate and adaptive immune response, and animal models further suggest that the lack of immune response leads to an increase in amyloid-? pathology, a phenotype that can be rescued with bone marrow transplantation. While some basic research on the genetic variants related to the innate immune response has been performed, no research to date has focused on the extreme somatic diversity of the adaptive immune response and its relationship with AD. We propose here as new investigators to AD research a pilot study to characterize the T-cell repertoire among Amish AD cases and controls. We will leverage local AD resources that include ongoing AD and successful aging studies recruiting Amish living in Ohio and Indiana who are ?80 years old. These resources also include existing genome-wide data from arrays and next-generation sequencing as well as imputation based on whole genome sequencing data. As important, the local resources are drawn from an active AD collaborative community eager to mentor and support new investigators forging original lines of research that potentially contribute to the prevention and/or treatment of disease. Against this backdrop, we propose the sequence the T-cell receptor beta (TCRB) chain of 30 Amish AD cases and 30 controls to characterize TCR diversity and its possible relationship with AD. These data will serve as key pilot data for larger studies of the adaptive immune response in the prospective and newly funded Collaborative Amish & Aging Memory Project (CAAMP) as well as future studies in diverse outbred populations.